Multicenter Study

. 2025 May 15;27(4):1102-1115.

doi: 10.1093/neuonc/noae260.

Machine learning-based prognostic subgrouping of glioblastoma: A multicenter study

Hamed Akbari¹, Spyridon Bakas^{2

3

4

5}, Chiharu Sako^{6

7

8}, Anahita Fathi Kazerooni^{9

10}, Javier Villanueva-Meyer¹¹, Jose A Garcia^{6

7

8}, Elizabeth Mamourian^{6

7

8}, Fang Liu^{12

13}, Quy Cao^{12

13}, Russell T Shinohara^{6

8

12

13}, Ujjwal Baid^{2

3}, Alexander Getka^{6

7

8}, Sarthak Pati², Ashish Singh^{6

7

8}, Evan Calabrese¹⁴, Susan Chang¹⁵, Jeffrey Rudie¹⁶, Aristeidis Sotiras¹⁷, Pamela LaMontagne¹⁷, Daniel S Marcus¹⁷, Mikhail Milchenko¹⁷, Arash Nazeri¹⁷, Carmen Balana¹⁸, Jaume Capellades¹⁹, Josep Puig²⁰, Chaitra Badve²¹, Jill S Barnholtz-Sloan^{22

23

24}, Andrew E Sloan^{25

26}, Vachan Vadmal²⁷, Kristin Waite^{24

27}, Murat Ak²⁸, Rivka R Colen^{28

29}, Yae Won Park³⁰, Sung Soo Ahn³⁰, Jong Hee Chang^{31

32}, Yoon Seong Choi^{33

34}, Seung-Koo Lee³⁰, Gregory S Alexander³⁵, Ayesha S Ali³⁵, Adam P Dicker³⁵, Adam E Flanders³⁶, Spencer Liem³⁵, Joseph Lombardo^{37

35}, Wenyin Shi³⁵, Gaurav Shukla^{6

8

35

38}, Brent Griffith³⁹, Laila M Poisson^{40

41}, Lisa R Rogers⁴¹, Aikaterini Kotrotsou⁴², Thomas C Booth^{43

44}, Rajan Jain^{45

46}, Matthew Lee⁴⁵, Abhishek Mahajan^{47

48}, Arnab Chakravarti⁴⁹, Joshua D Palmer⁴⁹, Dominic DiCostanzo⁴⁹, Hassan Fathallah-Shaykh⁵⁰, Santiago Cepeda⁵¹, Orazio Santo Santonocito⁵², Anna Luisa Di Stefano⁵², Benedikt Wiestler⁵³, Elias R Melhem⁵⁴, Graeme F Woodworth^{54

55}, Pallavi Tiwari^{56

57}, Pablo Valdes⁵⁸, Yuji Matsumoto⁵⁹, Yoshihiro Otani⁵⁹, Ryoji Imoto⁵⁹, Mariam Aboian⁷, Shinichiro Koizumi⁶⁰, Kazuhiko Kurozumi⁶⁰, Toru Kawakatsu⁶⁰, Kimberley Alexander^{61

62

63}, Laveniya Satgunaseelan^{61

62

63}, Aaron M Rulseh⁶⁴, Stephen J Bagley^{65

66}, Michel Bilello^{6

7

8}, Zev A Binder^{9

66}, Steven Brem^{9

66}, Arati S Desai⁶⁶, Robert A Lustig⁶⁷, Eileen Maloney⁹, Timothy Prior⁹, Nduka Amankulor^{9

66}, MacLean P Nasrallah^{6

8

66

68}, Donald M O'Rourke^{9

66}, Suyash Mohan^{6

7

8}, Christos Davatzikos^{6

7

8}; ReSPOND consortium

Collaborators, Affiliations

Collaborators

ReSPOND consortium:
Christos Davatzikos

Affiliations

¹ Department of Bioengineering, School of Engineering, Santa Clara University, Santa Clara, California, USA.
² Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
³ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁴ Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁵ Department of Computer Science, Luddy School of Informatics, Computing, and Engineering, Indiana University, Indianapolis, Indiana, USA.
⁶ Center for Data Science and AI for Integrated Diagnostics (AI2D), and Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Penn Statistics in Imaging and Visualization Center, and Center for Clinical Epidemiology ce and AI for Integrated Diagnostics (AI2D), and Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Center for Data-Driven Discovery in Biomedicine (D3b), Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹¹ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.
¹² Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁴ Department of Radiology, Duke University, Durham, North Carolina, USA.
¹⁵ Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
¹⁶ Department of Radiology, University of California San Diego, San Diego, California, USA.
¹⁷ Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁸ B-ARGO Group, Institut Investigació Germans Trias i Pujol (IGTP), Badalona (Barcelona), Catalonia, Spain.
¹⁹ Research Unit (IDIR), Image Diagnosis Institute, Badalona, Spain.
²⁰ Department of Radiology (CDI), Hospital Clínic and IDIBAPS, Barcelona, Spain.
²¹ Department of Radiology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA.
²² Trans-Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, Bethesda, Maryland, USA.
²³ Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA.
²⁴ Center for Biomedical Informatics and Information Technology (CBIIT), National Cancer Institute, Bethesda, Maryland, USA.
²⁵ Brain and Tumor Neurosurgery, Neurosurgical Oncology, Piedmont Health, Atlanta, Georgia, USA.
²⁶ Seidman Cancer Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
²⁷ Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
²⁸ Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
²⁹ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
³⁰ Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea.
³¹ Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
³² Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
³³ Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁴ Clinical Imaging Research Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁵ Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
³⁶ Department of Radiology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
³⁷ Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
³⁸ Department of Radiation Oncology, Christiana Care Health System, Philadelphia, Pennsylvania, USA.
³⁹ Department of Radiology, Henry Ford Health System, Detroit, Michigan, USA.
⁴⁰ Department of Public Health Sciences, Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan, USA.
⁴¹ Department of Neurosurgery, Hermelin Brain Tumor Center, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, USA.
⁴² MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
⁴³ School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.
⁴⁴ Department of Neuroradiology, Ruskin Wing, King's College Hospital NHS Foundation Trust, London, UK.
⁴⁵ Department of Radiology, New York University Langone Health, New York, New York, USA.
⁴⁶ Department of Neurosurgery, New York University Langone Health, New York, New York, USA.
⁴⁷ Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
⁴⁸ The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK.
⁴⁹ Department of Radiation Oncology, The James Cancer Hospital at the Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
⁵⁰ Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁵¹ Department of Neurosurgery, University Hospital Río Hortega, Valladolid, Spain.
⁵² Division of Neurosurgery, Spedali Riuniti di Livorno-Azienda USL Toscana Nord-Ovest, Livorno, Italy.
⁵³ Department of Neuroradiology, Technical University of Munich, Munchen, Germany.
⁵⁴ Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁵⁵ Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁵⁶ Department of Radiology, University of Wisconsin, Madison, Wisconsin, USA.
⁵⁷ Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA.
⁵⁸ Department of Neurosurgery, University of Texas Medical Branch, Galveston, Texas, USA.
⁵⁹ Department of Neurological Surgery, Okayama University, Okayama, Japan.
⁶⁰ Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
⁶¹ Department of Neurosurgery, Chris O'Brien Lifehouse, Camperdown, Australia.
⁶² Faculty of Medicine and Health, University of Sydney, Camperdown, Australia.
⁶³ Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, Australia.
⁶⁴ Department of Radiology, Na Homolce Hospital, Prague, Czechia.
⁶⁵ Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶⁶ GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶⁷ Department of Radiation-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶⁸ Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 39665363
PMCID: PMC12083074 (available on 2025-12-12)
DOI: 10.1093/neuonc/noae260

Multicenter Study

Machine learning-based prognostic subgrouping of glioblastoma: A multicenter study

Hamed Akbari et al. Neuro Oncol. 2025.

. 2025 May 15;27(4):1102-1115.

doi: 10.1093/neuonc/noae260.

Authors

Collaborators

ReSPOND consortium:
Christos Davatzikos

Affiliations

¹ Department of Bioengineering, School of Engineering, Santa Clara University, Santa Clara, California, USA.
² Department of Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
³ Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁴ Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, Indiana, USA.
⁵ Department of Computer Science, Luddy School of Informatics, Computing, and Engineering, Indiana University, Indianapolis, Indiana, USA.
⁶ Center for Data Science and AI for Integrated Diagnostics (AI2D), and Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Penn Statistics in Imaging and Visualization Center, and Center for Clinical Epidemiology ce and AI for Integrated Diagnostics (AI2D), and Center for Biomedical Image Computing and Analytics (CBICA), University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁰ Center for Data-Driven Discovery in Biomedicine (D3b), Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹¹ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, California, USA.
¹² Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹³ Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
¹⁴ Department of Radiology, Duke University, Durham, North Carolina, USA.
¹⁵ Department of Neurological Surgery, University of California San Francisco, San Francisco, California, USA.
¹⁶ Department of Radiology, University of California San Diego, San Diego, California, USA.
¹⁷ Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁸ B-ARGO Group, Institut Investigació Germans Trias i Pujol (IGTP), Badalona (Barcelona), Catalonia, Spain.
¹⁹ Research Unit (IDIR), Image Diagnosis Institute, Badalona, Spain.
²⁰ Department of Radiology (CDI), Hospital Clínic and IDIBAPS, Barcelona, Spain.
²¹ Department of Radiology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, USA.
²² Trans-Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, Bethesda, Maryland, USA.
²³ Central Brain Tumor Registry of the United States, Hinsdale, Illinois, USA.
²⁴ Center for Biomedical Informatics and Information Technology (CBIIT), National Cancer Institute, Bethesda, Maryland, USA.
²⁵ Brain and Tumor Neurosurgery, Neurosurgical Oncology, Piedmont Health, Atlanta, Georgia, USA.
²⁶ Seidman Cancer Center and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.
²⁷ Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
²⁸ Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
²⁹ Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
³⁰ Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea.
³¹ Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
³² Brain Tumor Center, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea.
³³ Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁴ Clinical Imaging Research Centre, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
³⁵ Department of Radiation Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
³⁶ Department of Radiology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
³⁷ Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
³⁸ Department of Radiation Oncology, Christiana Care Health System, Philadelphia, Pennsylvania, USA.
³⁹ Department of Radiology, Henry Ford Health System, Detroit, Michigan, USA.
⁴⁰ Department of Public Health Sciences, Center for Bioinformatics, Henry Ford Health System, Detroit, Michigan, USA.
⁴¹ Department of Neurosurgery, Hermelin Brain Tumor Center, Henry Ford Cancer Institute, Henry Ford Health, Detroit, Michigan, USA.
⁴² MD Anderson Cancer Center, University of Texas, Houston, Texas, USA.
⁴³ School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK.
⁴⁴ Department of Neuroradiology, Ruskin Wing, King's College Hospital NHS Foundation Trust, London, UK.
⁴⁵ Department of Radiology, New York University Langone Health, New York, New York, USA.
⁴⁶ Department of Neurosurgery, New York University Langone Health, New York, New York, USA.
⁴⁷ Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India.
⁴⁸ The Clatterbridge Cancer Centre NHS Foundation Trust, Liverpool, UK.
⁴⁹ Department of Radiation Oncology, The James Cancer Hospital at the Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
⁵⁰ Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
⁵¹ Department of Neurosurgery, University Hospital Río Hortega, Valladolid, Spain.
⁵² Division of Neurosurgery, Spedali Riuniti di Livorno-Azienda USL Toscana Nord-Ovest, Livorno, Italy.
⁵³ Department of Neuroradiology, Technical University of Munich, Munchen, Germany.
⁵⁴ Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁵⁵ Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
⁵⁶ Department of Radiology, University of Wisconsin, Madison, Wisconsin, USA.
⁵⁷ Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA.
⁵⁸ Department of Neurosurgery, University of Texas Medical Branch, Galveston, Texas, USA.
⁵⁹ Department of Neurological Surgery, Okayama University, Okayama, Japan.
⁶⁰ Department of Neurosurgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
⁶¹ Department of Neurosurgery, Chris O'Brien Lifehouse, Camperdown, Australia.
⁶² Faculty of Medicine and Health, University of Sydney, Camperdown, Australia.
⁶³ Department of Neuropathology, Royal Prince Alfred Hospital, Camperdown, Australia.
⁶⁴ Department of Radiology, Na Homolce Hospital, Prague, Czechia.
⁶⁵ Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶⁶ GBM Translational Center of Excellence, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶⁷ Department of Radiation-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁶⁸ Department of Pathology & Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 39665363
PMCID: PMC12083074 (available on 2025-12-12)
DOI: 10.1093/neuonc/noae260

Abstract

Background: Glioblastoma (GBM) is the most aggressive adult primary brain cancer, characterized by significant heterogeneity, posing challenges for patient management, treatment planning, and clinical trial stratification.

Methods: We developed a highly reproducible, personalized prognostication, and clinical subgrouping system using machine learning (ML) on routine clinical data, magnetic resonance imaging (MRI), and molecular measures from 2838 demographically diverse patients across 22 institutions and 3 continents. Patients were stratified into favorable, intermediate, and poor prognostic subgroups (I, II, and III) using Kaplan-Meier analysis (Cox proportional model and hazard ratios [HR]).

Results: The ML model stratified patients into distinct prognostic subgroups with HRs between subgroups I-II and I-III of 1.62 (95% CI: 1.43-1.84, P < .001) and 3.48 (95% CI: 2.94-4.11, P < .001), respectively. Analysis of imaging features revealed several tumor properties contributing unique prognostic value, supporting the feasibility of a generalizable prognostic classification system in a diverse cohort.

Conclusions: Our ML model demonstrates extensive reproducibility and online accessibility, utilizing routine imaging data rather than complex imaging protocols. This platform offers a unique approach to personalized patient management and clinical trial stratification in GBM.

Keywords: glioblastoma; machine learning; mpMRI; prognostic subgrouping; survival.

© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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References

1. Ostrom QT, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2014–2018. Neuro-Oncol. 2021;23(12 Suppl 2):iii1–iii105. - PMC - PubMed
1. Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318(23):2306–2316. - PMC - PubMed
1. Board WCoTE. WHO Classification of Tumours. Vol 6. 5th ed. Lyon (France): International Agency for Research on Cancer; 2021.
1. Telloni SM. Tumor staging and grading: a primer. In: Espina V, ed. Molecular Profiling: Methods and Protocols. New York, NY: Springer New York; 2017:1–17. - PubMed
1. Ludwig JA, Weinstein JN. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer. 2005;5(11):845–856. - PubMed

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Machine learning-based prognostic subgrouping of glioblastoma: A multicenter study

Collaborators

Affiliations

Machine learning-based prognostic subgrouping of glioblastoma: A multicenter study

Authors

Collaborators

Affiliations

Abstract

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical